Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome to What I Tell My Patients: New Treatments and Clinical Trial Options, as today we’re going to focus on the management of chronic lymphocytic leukemia. We were talking about the fact that we know about a third of you have only been in oncology less than 2 years, and Dr Hart and I want to let you know that you just listened to Crosby, Stills, Nash & Young and actually the Beatles. Have you ever heard of them? That was what you just heard. I’ve mentioned that this is the first time I’ve actually done a live meeting in 2 years, and the main thing that got me back was I want to hear that music.

Anyhow. All right. So let’s talk a little bit about what we’re going to be doing here today. We have a great faculty. In a moment we’ll introduce them and chat with them a bit before we kind of get started here. For the clinicians here in the room, on your iPads you have all the slides that we’re going to be showing today, and actually there are many that we aren’t going to show for you to take a look through. There’s a survey that we’d like you to take on that, and we’re going to show the results of that as we go through a couple of them. And if you have any questions or cases you’d like to run by the faculty you can type them in there, and also do the evaluation.

And for our many people who are online today you can do the same thing in the chat room, and of course we expect a lot of people end up watching the replay of this because we’re video recording all of these meetings here today. And in fact, this is our sixth of 10 meetings that we’re doing here over these 3 days. We visualized this really as an integrated experience. It’s not just about the cancers that we’re discussing but about oncology nursing in general, and cancer research particularly, and where things are heading.

Here’s kind of a road map of where we’ve been and where we’re heading. Tomorrow we’ll be finishing out with programs on cervical and bladder cancer and addressing the question of where are we going to be in 10 years in taking care of our patients. We actually have a couple other programs we couldn’t squeeze in here we’re going to do by webinar in the next couple of weeks.

One of the themes that we want to get into today is why was it different to take care of this patient compared to another patient with the same cancer situation but a different person. How do we individualize that?

So I’m going to actually introduce the faculty. We’ve had a tradition over the years when we introduce the faculty we ask them to comment a little bit, particularly for the people who are new to the field, about how they get away from the stress and the challenges of their work. This is a question you see on a lot of burnout surveys, which just often ask you how you feel, how many times a week or year you feel certain things. And we asked you all how often do you feel very satisfied with your work: never or every day or somewhere in between. And interestingly I mean you’re in the right place, I guess, because it looks like you feel a lot of satisfaction, probably a lot of stress and challenges as well. But we’ll see examples of that as we go through this.

So we’re going to start down there with Dr Hart. He kind of pitched in. One of our faculty got a little viral illness. I’m not sure if you’ve heard of it. It’s kind of going around the last couple years. But she’s okay. She wanted to come in virtually, but actually we got Dr Hart, and Dr Hart’s very unusual in that he’s a researcher but also is in a general medical oncology practice in the Florida Cancer Specialists, so he sees everything. So we’re going to try to bring the perspective because CLL is a disease that’s seen very commonly in general practice.

So Lowell, how do you get away from things? You were talking this morning about exercise.

DR HART: Yeah, I exercise and also I have to mention I spend as much time as I can with my granddaughters and my new grandson, which is — they are the light of my life, for sure. And it was physically possible to do it I would recommend skipping children and going directly to grandchildren because — I haven’t out how that can be done, but it would be a great idea. A huge improvement.

DR LOVE: I actually like them both. I’ve got a 2-year-old granddaughter also. Wow, so amazing. So Anthony?

DR MATO: Great. Nice to be here. To get away and destress I like going to the Jersey Shore. I have a place there. And then most of the nurses in our practice all bought a Peloton simultaneously so they talked me into it, and so now I have one. We’ll see how that works.

DR LOVE: Actually, last night they were saying the lung cancer program at Yale has a Peloton group, that they work together. So I guess you guys are doing it too at Memorial. Amy? I’m sorry, go ahead.

DR MATO: I was going to say I think they wanted me as part of the group so I will always be last place.

DR LOVE: Amy?

MS GOODRICH: So I am getting ready to put in a huge vegetable garden. I have all my seeds started and my little sprouts are coming up in the house, and just looking forward to getting out and gardening. And my daughter also plays very competitive softball. She’s in high school. So we travel all the time, and I’m the scorekeeper because I go off the chain if I’m not focused, so she likes me to take score so I’m not yelling. She doesn’t mind when I yell at her, but I yell at other girls too, so it keeps me on the chain.

DR LOVE: Camille.

MS BALLANCE: Good afternoon. Great to be here today. Well first of all, I make sure that I actually take my vacation time. I think that’s number 1. I think it’s easy to get into a habit of like, yeah, I haven’t had a vacation in a few months, and so that helps. I like to get outside and walk, especially in the nice spring weather, and I like to treat myself at the spa. Yes.

DR LOVE: So again, for those of you who are new to the field, do this stuff. You need to.

Overview of Chronic Lymphocytic Leukemia

DR LOVE: So let’s talk about CLL a little bit. And here’s where we’re heading. First we’re going to chat a little bit, kind of provide an overview, and then we’re really going to dig into some of the new developments in the field that really completely revolutionized this disease, maybe like no other in oncology. This is the prototype of what we’re looking for.

And actually, even before we get started, Lowell, it’s so hard for people to get a grasp of what it was like to take care of patients with this disease before this new wave of novel agents, BTK inhibitors, venetoclax, came to a head. It’s hard to believe. And we used chemotherapy all the time in CLL. We never use chemotherapy, and that’s a fairly dramatic change.

Lowell, can you kind of put in perspective what you’ve seen in terms of CLL?

DR HART: Oh, yes. I mean when I started it was pretty much chlorambucil was generally — or some other alkylating agent, occasionally oral cyclophosphamide or things were the drugs that we used. And then fludarabine came along, and we started using that, and then rituximab. So tremendous change in how the disease has been — and we also at that time didn’t really — we had similar indications for who needed to be treated versus who didn’t, but we didn’t understand all the molecular underpinnings of the disease and the different subtypes and who’s got p17, who’s got — or p53 and all of these other mutations and things that we understand now.

So it’s really tremendously changed, and this is even before we get to the crazy, wild things like bispecifics and CAR T, et cetera, et cetera. So really tremendously changed.

DR LOVE: And we’ll get into all that in a second. And Anthony, you’re the head of the program — CLL program at Memorial. I remember a few years ago I interviewed Hagop Kantarjian from MD Anderson, a really legendary figure in the field, and he said, “I think that CLL is going to become the new CML, and that maybe people are not going to die of this disease. They’re not going to get chemotherapy. They’re going to get targeted therapy.” Is that your vision, or do you think we can actually cure CLL?

DR MATO: I think that that’s partially true. I think biologically CLL’s probably more complicated than CML, and so the mechanisms of resistance are probably a lot more complicated. But I think certainly we can go sequentially for a decade or longer for most patients just on the currently-approved agents. Maybe the combinations will cure patients. Maybe we don’t need to do that. But we’re certainly heading in that direction.

DR LOVE: Amy, I’m curious about your perspective. And one of the challenges of CML — CLL that we don’t have in too many cancers is the most common initial therapy is to observe the patient and not treat the patient at all. And I wonder kind of what you see in terms of how people respond to this idea of observing yourself when you have a cancer.

MS GOODRICH: Right. So it’s very variable. Some people are really fine with that active surveillance or watching and waiting and others you really have to talk through it and explain to them the criteria for treatment, which we will talk about here, and really that they’re not going to live longer by treating them the day they get diagnosed versus when they actually need treatment. I also think that especially with this older population I try to say to them do you know somebody with prostate cancer who’s just being observed. That this is another one of these slower-growing malignancies where we don’t necessarily have to do anything and can observe.

DR LOVE: So Camille, I’m curious also how you find taking care of patients with CLL. Now not only do we have to deal with the CLL but also the risk of infection. COVID was a big issue, and it continues to be a big issue. We’ll mention that briefly. Again, when you think about cancers that have been affected by COVID, again I put CLL way up there. We’ll talk a little bit about kind of what happened, particularly in New York when things got started. Any comments about dealing with the issues of infection in patients with CLL?

MS BALLANCE: Yeah. So that’s — that is a conversation that I have constantly. And once COVID started it was — it was just a longer, more intense conversation of making them number 1 understand what their disease is and why they basically have a cancer of their immune system. They have a chronic cancer of their immune system, and it can be underactive, and it can be overactive. And so I really try to make them understand why they’re at higher risk than the average person, and then also just making sure that — talking about infection prevention and those things.

And then also making sure, that now that we have oral antivirals and things like that, making sure if they get COVID to call us immediately so we can get them started on a medication.

DR LOVE: And we’ll talk a little bit more about the prevention and management in patients who actually develop COVID.

We put a number of self-assessment questions in all of these programs here, and a lot of these we asked in the pre-meeting survey, but we’ll go through some of these. So one is the issue of treating somebody who’s asymptomatic. You have an abnormal blood count, abnormal CBC, but you feel very well. Lowell referred to some of the variations or the subtypes within CLL, and one, Anthony, is (del)17p/TP53. What about that in a patient who’s asymptomatic? We know these patients don’t respond as well to treatment. They don’t respond at all to chemotherapy. And what about the patient who just has a high white count? Either of these 2 things in a patient who feels well and is asymptomatic would get you to treat, Anthony?

DR MATO: If a patient was asymptomatic I would not treat based on either of those. There’s no indication based on genetics. There’s no absolute cutoff for the white count.

DR LOVE: How do patients respond when they have a white count of 200,000 saying we’re going to watch you?

DR MATO: If they’re asymptomatic I think they’re happy to be observed. It’s more counseling, but certainly think that’s probably one of the greatest educational things we do is say that there is no cutoff.

DR LOVE: And we know, again, that these patients don’t respond well to chemoimmunotherapy much better.

Amy, what about prevention of COVID? We have the Evusheld antibody. Right now we have kind of gone back and forth with omicron, and we — we asked a lot of other people to fill in for the doc, and a couple of them had COVID, but it’s obviously very different than things were a year or so ago. Where do you — what’s going on right now, particularly with your patients with CLL, Amy?

MS GOODRICH: So we are doing antibody testing on everyone and offering it to anybody who does not have immunity. And one of the things that we have started doing is if patients are not vaccinated, and we’re going to start therapy, particularly with an anti-CD20 monoclonal antibody, we are, if we can, delaying therapy for them to get vaccinated and started to mount some immunity before we start treating them.

DR LOVE: So a couple other issues here. Here are some demographics in terms of CLL. These are generally older patients, median age at diagnosis of 72. You see it a little more in men. We talked a little bit about indications. Lowell, can you comment on the clinical scenarios that get you to want to start treatment, not just the specific ones related to nodes and cytopenias, but also autoimmune complications?

DR HART: Right. All of these things are — this is a little bit in flux, and it can change a little bit with patient preference, obviously, and other comorbid conditions and things that they have. And again, it’s — disease-related symptoms are important. If they have bulky disease, generally speaking it’s kind of a lymph node group overall over 10 cm or a spleen that’s down by more than 6 cm, and to me the biggest thing is that they have progressive bone marrow failure. If their platelets are — and I always tell the patient, if the bad cells are going up and the good cells are going down that’s a bad thing. If it’s just the bad cells going up, since their — I explain this to patients all the time, since they’re kind of lazy, yes they’re malignant cells, but they’re lazy malignant cells, and if they’re going up and the good cells are staying stable, then you don’t have to be treated.

So bone marrow failure’s a big thing. Rapid — again, this is a little bit in the eye of the beholder, rapid lymphocyte doubling time usually portends that at the very least you’re going to have to watch them more closely and get them ready to get treated. And if they have these autoimmune complications, they can get autoimmune hemolytic anemia, they can get ITP, things like this, if they’re not responding. So those are all things. And of course they have the classic B symptoms: fever, night sweats, and weight loss. If they have a combination of these systemic symptoms you can kind of get the idea about who’s going to really need treatment and who isn’t.

And there are plenty of people who do not need treatment for a long time and maybe not ever. My absolute all-time record patient, 102 years when he died, had CLL. I never treated it. And my — I was mentioning before, my late brother had CLL and died with the disease not of the disease, and he was never treated.

DR LOVE: Anthony, how often do you see people die of CLL nowadays, and what do they usually die of?

DR MATO: How often do you see them die of CLL? It’s pretty uncommon, actually. Pre-COVID the number of patients in our practice who actually died of a CLL-related complication was really low, I mean under 5 patients per year, and we have a large practice. With COVID that increased for a while, but now it’s thankfully kind of back to that baseline, where our practice is always growing, and we really fortunately don’t have any issues.

If a patient dies of CLL it’s usually like an ultra-refractory patient, multiple targeted therapies, somebody who’s transformed, but the most common cause of death in CLL is actually infection still, even without COVID being involved.

DR LOVE: Interesting. So Camille, we asked you to make a few comments on CLL management. Can you please comment a little bit?

MS BALLANCE: Absolutely. So yeah. So bottom line, CLL patients are at risk for infection. Before COVID they were at risk for infection. And so particularly respiratory infections. I feel like before COVID from like October to March I was running a flu clinic. They would come in for regular follow up, and they would have symptoms. There was a lot of sinusitis and those types of things. So when COVID started happening, obviously, it was concerning, and some patients didn’t do so well.

Also several months into the pandemic we got some data that showed that the mortality rate for patients with CLL that got COVID was like 30%, which is really, really high. So making sure the patients understand their risk, and their families. That’s really important, too. Their families need to understand why they’re so at risk. The patients need to be vaccinated, but their families also need to be vaccinated, right, to help lower their risk of contracting the disease. So that was really important.

Kind of what Amy touched on earlier, vaccine timing if they’re going to start treatment soon, making sure that they get their vaccines beforehand. CLL patients in general, they don’t always have a robust response to vaccines because they have a cancer of their B-cell lymphocytes. B-cell lymphocytes make immunoglobulins, immunoglobulins help make antibodies, so they don’t, but we want them to have every single protection possible. So making sure that we give them that chance.

Also treatment decisions. When we give — and we’re going to talk about this later, when we give monoclonal antibodies, the anti-CD20s, we’re killing all of their — we’re killing their B cells so they’re not going to have any of the good ones they may have had swimming around. They’re going to go, right, with the treatment, and that can last for up to a year after their last infusion. And so that’s a teaching point. They need to understand that. They need to understand why whereas they work incredibly well at putting their disease in control it can also make things more complicated, particularly in a COVID-19 world.

Comorbidities. It’s important to look at the patient’s comorbidities, if they have diabetes, if they have COPD, if they have really bad uncontrolled hypertension, and that’s going to put them at more risk, right, for severe illness and death.

And then a lot of the psychosocial issues that we’ve been dealing with is a lot of these patients have been social distancing for 2 years, right, or they have occasional meetings with their family outside. Now the Evusheld has helped with that. If they’ve made antibodies to the vaccines that has helped. But assessing if — first of all assessing if they can social distance, right? If they’re living in a homeless shelter, if they’re living in a house — a small house full of people then that’s not really an option for them. And then isolation that comes along with it. A lot of these patients have a lot of increased anxiety and depression, especially because there’s been so many times in this past 2 years where we’re like — it felt like there’s no end in sight, and that’s triply, quadruply so for these patients.

And then when we’re talking about it we have to be honest with our patients about that they do need — that they do need to get vaccinated. They do need to be careful. Their family needs to be vaccinated, but of course we have to assess their beliefs about that, right? That has been a controversial topic over the past couple of years, and you kind of have to walk softly and carry a big stick, if you will, with some patients because they will get upset if you even — at least in my neck of the woods I’ve had that experience. And so it’s being honest with them and being direct, but also trying not to be judgmental and obviously, obviously, not getting in an argument, right? That doesn’t go anywhere. You just have to kind of assess where they are and do the best you can, so…

DR LOVE: So Amy, another issue that comes up is even more is patients who get COVID and are on treatment. At one point, actually there was interest in looking at Bruton tyrosine kinase inhibitors to treat COVID because of the immune effect. That kind of didn’t pan out. But I’m curious at Hopkins what you do. A patient tests positive, they’re asymptomatic, testing positive, they have mild symptoms, serious symptoms, what do you do, and does it vary based on what kind of treatment?

MS GOODRICH: So if they’re on therapy we are — so now we’ve got the oral agents, but prior to that we were bringing — even the asymptomatic people who were on therapy we were bringing them in and giving them whatever monoclonal antibody was effective against whatever strain we were dealing with because we know that these people are at high risk for significant morbidity and mortality. And we’ve had people get very sick and take 6 months to clear the COVID, they remained positive for extended periods of time, so we really try to jump on them quickly to get things under control and keep them from having severe illness.

DR LOVE: What are you doing now? Lowell, what do you do in your practice when you have a patient who develops COVID, they’re on a BTK inhibitor or whatever, they’re being treated, how do you manage those patients?

DR HART: Well, lately, obviously, the oral agents are out, so those are available now, which is good, and they’re easier to get, so generally speaking that’s what we’ve done. And obviously if there’s somebody who’s — we don’t generally hospitalize them unless we have to, but we’re going to monitor them very closely.

DR LOVE: Do you stop therapy?

DR HART: I would stop — well, it depends what therapy they’re on. I mean if they were due for a monoclonal antibody or something I would delay that. I don’t know what they would do at MSK or other places, but I wouldn’t necessarily stop an oral therapy.

DR LOVE: Yeah. And Anthony, maybe you can reflect back. I can recall talking to you all a couple years ago when New York was really the initial hotspot. It was scary talking to you all. Maybe reflect back on that and where we are today. Maybe comment a little bit, too, on something Amy was talking about, which is the anti-CD20 agents, so particularly obinutuzumab, which you’re going to hear combined with venetoclax, also rituximab, a little bit more about are you using them less frequently now. Are you using them for shorter durations? Maybe reflect back also about what happened 2 years ago there.

DR MATO: Sure. Two years ago, when COVID first hit, our research in CLL was essentially paralyzed, we couldn’t do anything, so we decided we’d better start studying COVID because it was the most timely topic for patients with CLL at that moment. So we actually published those papers that had the 30%-percent mortality. And actually it’s been most helpful citing that literature to patients who are not that eager to get vaccinated when you kind of remind them what the data looked like a few years ago. But certainly there were no options for patients. It was a nightmare, particularly in New York, but the rest of the country.

Today it’s a different story. Thankfully there are very, very few patients with CLL I can think of in the last 12 months who have died, and it’s mostly because of what we’re talking about, the oral agents or the monoclonal antibodies. I mean I was kind of listening to you talk about it. It seemed so routine, like oh I just prescribed a monoclonal antibody for a virus. We never did that before in medicine. It’s like that was only a — that was science fiction that you could even think about giving an anti-CMV antibody or something like that. They existed but you could never get them.

So now patients are doing fine. I do say one comment I would make is the oral agents do interact with the CYP3A4 pathway, and so you do have to stop the BTK inhibitors or venetoclax or a lot of experimental meds like while they’re on that for 5 days or whatever it is —

DR HART: Yeah. That’s a good point.

DR MATO: — just to minimize complications.

Regarding the CD20s, I think 2 years ago I would have said yes I’m holding back or giving less. Today I just give whatever I think is the most appropriate therapy the way it’s supposed to be written because I think the options for patients if they happen to get sick are much lower. I’m probably not withholding therapy now for vaccines, mostly because we’re in this cycle where every like 4 months they’re getting one anyway so it’s really hard to time it. But I get your point, early on it made a lot of sense to delay a month or so just to try to get some antibody response.

DR LOVE: So Amy, another outcome that we’ve seen in the last couple years, I don’t hear too many people talking about it, but maybe the greatest change in the history of medicine has occurred in the last 2 years, in my view, in terms of the introduction of telemedicine. We all knew that it could be done, it just we couldn’t do it. And now the genie’s out of the box.

I’m just kind of curious what your perception is, Amy, in terms of how telemedicine’s altered your practice and moving forward your vision. And we’re going to talk more about this Saturday morning when we talk about the future of oncology, of what’s it going to be like. Are we really going to go back the way it was 2 years ago or are we going to really try to make this more effective for patients? Any thoughts?

DR LOVE: Right. I mean well certainly when we were in the thick of COVID telemedicine really kept us going and kept a lot of patients out of our practice areas. Today, in Maryland, it is very adopting — and it’s different state by state, so Maryland is very adopting of telemedicine, and I think that it will be here to stay. In the state of Maryland there is a place for telemedicine in CLL: for those long-term follow up patients, for the folks who are quite elderly and have transportation issues. I would say I, today, whereas before I was probably seeing about 30% of my — in the thick of COVID about 30% of patients via telemedicine. It’s probably down to less than — it’s probably somewhere around 5% at this point. It’s not as prevalently being used, but there is definitely a role for telemedicine in the world of CLL.

Camille, another outcome, I think, of COVID is we always knew the family and loved ones were so important to patients, but we learned a lot more about it when you pull them away. And there was a long period of time when we didn’t have visitors in clinic, we didn’t have visitors —

MS BALLANCE: Yes.

DR LOVE: — and very, very difficult. Any thoughts about what that was like and kind of reflecting back did it reinforce for you the importance of family?

MS BALLANCE: Yes. So early on — we had no family in the treatment room until about a month ago, basically. That we handled. People weren’t happy with it, of course, but we handled it. But also there were no family in the exam rooms, which was challenging, right, because if you’re dealing with — you’re dealing with a 75-year-old gentleman, he’s by himself, they can get the — they can get the wife on the cell phone, but she’s not always there, and you can’t hear them, and it’s crackling. And it’s awful trying to do education on a cell phone. I’m sorry.

And then — or we’re giving — we’re giving test results. We’re giving CT scan results or whatnot, and then we have like family members calling up. They’re crying because they didn’t know what was going on because the patients did tell them what was going on. They didn’t remember half of what we said. So we very quickly were like we have got to get at least — we’ve got to allow 1 person in this exam room just to help with — help with the understanding or with new patients. It's a big part of what we do, or what I do, is try to get them to understand what their disease is, honestly, and then the treatment is a whole other thing. So family is key and super important with that.

Bruton Tyrosine Kinase Inhibitors

DR LOVE: So let’s dive into the specific therapies of CLL and really what’s revolutionized first-line therapy has been both Bruton tyrosine kinase inhibitors, plural. We started out with 1, ibrutinib, now we have several. And then venetoclax combined with the anti-CD20 antibody we were just talking about, obinutuzumab, and then we’ll talk about future strategies, and there’s a lot going on in that respect.

Let’s talk about BTK inhibitors. And so here are a couple self-assessment questions. So Amy, this is a phenomena you see with all the BTK inhibitors, we said ibrutinib, which is that usually you see an increase in the white count, kind of counterintuitively. I guess they’re thinking it’s coming out of the marrow, is circulating. I never really understood. Maybe we’ll see what the docs think about that.

But from a clinical point of view can you kind of talk about what happens and how you reassure patients that it’s good, it’s okay?

MS GOODRICH: Yeah. I try to talk about this before we start a BTK inhibitor and explain to them that the lymph — they’ll see their lymph nodes rapidly shrinking, and that those lymphocytes are moving out of the lymph nodes and into the peripheral blood. So and this, it probably happens in about half of patients, just as a ballpark, but they all need to be ready for it because it’s really disturbing if you don’t prep them for that, especially those folks who have their spreadsheets of their 10 years of lymphocyte counts.

DR LOVE: And Lowell, this phenomena of the bump in white count sometimes can be fairly prolonged. How do you reassure patients? It kind of seems counterintuitive that you’d be seeing an increase in white count from therapy, and yet maybe the other symptoms, their cytopenias are getting better. Any comments?

DR HART: Right. Well it’s just a matter of explaining to them that these are cells coming out of the body, getting into the blood stream, and they’re going to go out. And that, again — I tell them, again, that these are the lazy cells, that they’re lazy. They don’t know how to fight infections. They don’t know how to fight other cancers, which is a bad thing, but it’s good that they’re not going to necessarily destroy your body when they get in the blood stream. So I think they can usually follow that.

DR LOVE: So Camille, BTK inhibitors. Should they be discontinued prior to surgical procedures and after surgical procedures?

MS BALLANCE: Yes. Absolutely yes.

DR LOVE: For how long, and what’s the reason?

MS BALLANCE: It depends. So if it’s something that’s — it’s 3 to 7 days, depending on what they’re getting done, right? So if there’s going — if there’s a really high risk of bleeding, like if they’re getting open heart surgery, they need to hold it for a week before and a week after. That comes with its own set of challenges because they can — some of the patients have withdrawal symptoms coming off the BTK inhibitor, so you have to prepare them for that. Some patients don’t, but some of them do, like joint aches, and sometimes they have low-grade fevers.

But yeah, I’ve had a patient, actually, that didn’t hold his ibrutinib prior to his cataract surgery. Cataract surgery is very common. They do it all the time. He had a horrible complication. He came into see me. His eye was bloodshot red, and I had a very hard time holding my poker face. I was like what’s going on with your eye? So he had to go to a specialist and all of this. And he had been counseled, but he was afraid to hold it because he was worried his CLL would come raging back. So that was — yeah.

DR LOVE: Anthony, how do BTK inhibitors increase the risk of bleeding, and what do you see clinically? I’ve heard a lot of people talk about bruising on the extremities, but do you see serious bleeds, CNS bleeds, et cetera?

DR MATO: Thankfully not frequently, but it’s a class effect. I think the bleeding risk is most frequently associated with ibrutinib because there’s just more literature, but all of the BTK inhibitors can affect platelet binding, or the function of platelets, particularly when they’re binding to collagen, I believe. And so it’s an antiplatelet agent in addition to what it’s doing in the B cells, and so just like you’d hold an aspirin for a procedure you need to think about the BTK inhibitors in the same way.

DR LOVE: When you start a patient on a BTK inhibitor, we’re going to get into the various ones that are available and how they differ, but when you initiate therapy, in general for a “typical patient” although I don’t know if there really is one, what are you expecting in terms of disease control on average. How long can you expect they’re going to be under control?

DR MATO: Great question. The longest-term follow up data we have now is for ibrutinib, so that’s probably the best example. There’s 7 to 8 years of long-term follow up. The median progression-free survival hasn’t been reached at 7 or 8 years, and about 62%, I’m forgetting the exact number, are still in remission at that timepoint. So that’s the baseline, I think, and we don’t yet know with the more recent second-generation inhibitors whether or not it’ll be better. But the curves for acala, for example, also look quite excellent at 4-year follow up that we have now, so we’ll see with longer term if they look even better.

DR LOVE: And just to put in context, by far and away the most common therapy for CLL prior to this, for most cases, was chemotherapy, bendamustine, and rituximab. What would you be looking at — what were you looking at then in terms of how long would you see disease control?

DR MATO: It varied. This is where the prognostic markers were developed, and so we talk about 11q and IGHV status and (del)17p as being poor-risk features, but they were really developed in a time period when patients were all being treated with chemoimmunotherapy. So if you were a perfect patient, IGHV mutated, no bad risk factors, much longer remission duration, 4, 5, 6 years. If you had a 17p IGHV unmutated probably under 2. So it really — it was really different. It just depended on the molecular profile, and also their comorbidities. How easily could you deliver let’s say 6 cycles of therapy?

DR LOVE: And then, Amy, that kind of gets into some of the newer BTK inhibitors, and particularly acalabrutinib, which is actually directly compared to ibrutinib in a trial. And zanubrutinib, another BTK inhibitors that’s been compared, both seeming to be less toxic, or less side effects. What are the kinds of problems you see with BTK inhibitors, particularly quality of life issues? Arthralgias, skin problems. What are some of the day-to-day issues you see with these agents?

MS GOODRICH: Yeah.

DR LOVE: And do you see differences between say acala and ibrutinib in that way?

MS GOODRICH: Right. So in general ibrutinib was our first-generation drug and really has the most off-target effects. And then the ones that have come after are more specific to BTK; have less off target, so less side effects.

The things that I prep patients for: nausea, diarrhea, bleeding for sure, and then as they go on some neutropenia, some other cytopenias. They need to understand that AFib is a risk factor here, so just signs and symptoms of AFib. But really initially it’s the GI system and it’s that minor bleeding that patients need to be ready to report and that we need to be ready to tweak.

The arthralgias are also an issue — patients, that really impacts their quality of life. Physical therapy will help that, some acetaminophen. You’ve got to be careful about NSAIDs because of that risk of bleeding, so this is an acetaminophen-only crowd whenever humanly possible.

DR LOVE: So Camille, people were starting to switch over to acalabrutinib just based on clinical experience, but I think once they saw the data that really confirmed what people were saying, which is it seemed to be better tolerated, there was even more of a switchover. But there was a practical problem with acalabrutinib that currently exists and maybe won’t exist, which is that you can’t give it with PPIs, or proton pump inhibitors. There was actually a presentation at the American Society of Hematology Meeting in December where they looked at a preparation that will not require — that you’ll be able to take PPIs with. But how much of a problem or issue has this been? A lot of people are taking PPIs.

MS BALLANCE: Yeah. So I think that’s the key, is that a lot of people are taking them. It’s assessing the reason of why they’re taking them. Do they even know why they’re still taking them? Can we try them on Pepcid? Can we get them off of it? If they have a serious issue where they can’t go off their proton pump inhibitors then obviously acalabrutinib, at this point, is not for them because it needs that acidic environment in order to work.

But a lot of times I find even just kind of weaning them off or stopping their proton pump inhibitors and trying other things tend to work. I have several patients that have done that on acalabrutinib and have done very well, so…

DR LOVE: So Anthony, Amy referred to cardiac issues, and these are probably the greatest concern that we’ve had with these agents, particularly ibrutinib. She mentioned atrial fibrillation but also ventricular arrhythmias. We had a case of a patient who had sudden death syndrome, recuperated, was on — presumably had a ventricular arrhythmia from ibrutinib.

Can you talk a little bit about the cardiac effects? We’ve done programs with your cardiology people at Memorial, who say this is a huge, huge issue. First of all, maybe review what atrial fibrillation is, how it’s managed, and how it gets involved with BTK.

DR MATO: Sure. There’s — of the top of my head there’s at least 3 cardiovascular issues, maybe 4, depending on how you look at it, when you think about the BTK inhibitors, atrial and ventricular arrhythmia, so whether the rhythm is coming from the atria of the heart or the ventricular area. AFib is probably the most common arrhythmia associated with BTK inhibitors. V-tac or VFib, life threatening, thankfully rarely happens. But then hypertension is probably the sleeping giant of them all because it probably causes arrhythmia in addition to its long-term toxicities in the vascular system.

And then if you add bleeding to the mix, while it’s not a cardiac issue, if you have a bleeding risk it might make it harder to minimize the risk of developing a stroke when you have atrial fibrillation, which is generally either managed with aspirin or anticoagulants. So the incidence is different between the different BTK inhibitors, and we can talk about that based on the head-to-head data. This is probably an area where oncologists are just not great at managing these issues.

We’re not well versed in AFib management or what’s the state of the art or hypertension, yet all of our meds interact with the meds that the cardiologists or primary care doctors prescribe, and it’s also a situation where we might tell a patient you’re hypertensive, your blood pressure’s 160, come back in 3 months, but make sure you see your PCP. They don’t see them, or they do and the primary doesn’t take it as seriously, and the next thing you know 3 months later they’ve been hypertensive for another 3 months.

And there is literature out of several groups, OSU, others, that show like it’s not a silent hypertension. These people tend to get more heart attack, stroke, peripheral vascular disease, so it’s real. And then the last thing I’ll say is that no one really knows how to manage the hypertension well. Most of our patients end up on 2 or 3 agents, so that’s an issue. It’s a refractory-type hypertension.

And then for AFib management, I mentioned the anticoagulation issue, beta blockers are the standard of care. Rate control is really preferred over rhythm control.

DR LOVE: So Lowell, another issue are patients who are on anticoagulants. Maybe they already had AFib, and they’re on an anticoagulant. We talked about the bleeding risk. The patient walks in, they’ve got CLL, they need to be treated, but they have a history of AFib. They’re on anticoagulation. What do you do?

DR HART: Yeah. That’s a tough problem. That’s a tough problem if they need — I mean I would. If they absolutely — I mean that’s something where it’s good to have an oncocardiologist or cardio-oncologist, which happily we now have in Fort Myers, Florida, believe it or not. And those are not commonly available outside of academic centers, but it’s a tremendous advantage to have someone who’s a cardiologist not just interested in doing lots of caths and procedures and things but interested in taking time to think about these cases. I mean I think that’s — potentially patients, if they couldn’t come off of anticoagulants, I mean there are other choices for CLL. I would think about another choice of drug if there was no other way around it. I mean I think it’s certainly something where I would have had less problems with acala than with ibrutinib. But still, I think it would be potentially an issue.

DR LOVE: Anthony, how do you handle that? And I’ve heard people say they approach it differently depending on the type of anticoagulant. Does that make a difference to you?

DR MATO: Well, warfarin is off the table because the major bleeds that you were mentioning early, the subdural hematomas, the Grade 3, 4, or 5 bleeds that happened early on, were largely on patients who were on warfarin. So as long as they’re not on that I really have comfort in prescribing a BTK inhibitor plus whatever. I think the bleeding risk is slightly increased, but if you think it’s the best therapy for the patient that would not stop me.

DR LOVE: So Amy, it’s really hard to grasp how much BTK inhibitors have affected this disease. It’s just mind-blowing when you think about it. However, there are still many issues that come up in the treatment of these patients, as we’ve just been talking about, serious issues. Can you talk a little bit about some of the things you prepared some thoughts about what you think about when you’re about to sit down with somebody about to start a BTK inhibitor?

MS GOODRICH: Right. So we covered the common side effects that I talk to patients about. I make sure they have antiemetics. I make sure that they have got some antimotility drugs at home so if they develop diarrhea. Taking it at night can be helpful, when their gut is getting ready to rest, to minimize those GI toxicities. Of course the bleeding, and really the thing is making sure that patients know when to — what triggers calling us. If they’re just flossing their teeth, and there’s a little blood on the dental floss, we don’t need a call. But if they have a nosebleed that won’t stop or something that’s out of the realm of manageable they need to be letting us know.

I really try to see patients very frequently during that first month or 2, and some of it depends on how reliable I think the patient is going to be with reporting. People that I’m not real confident are going to let us know what’s happening or being adherent to their oral schedule, I see them weekly. You’ve got to watch counts initially, closely initially, and then that can taper off.

But I also have the pharmacist look at their med list with me. That is a huge issue with these patients. They will tell you their prescription medications. They will not tell you necessarily all of the other supplements that they are taking, so you’ve really got to fish that out of patients so that you really understand — they don’t consider those medications. That can be a real challenge figuring out what they’re actually taking. And if they’re on all these homeopathic things, and lots of people who have been observed for a while see nutritionists, and they’re on all of these — all of these supplements. We really just ask them to stop because we don’t know. We know the drug-drug interactions for prescription drugs. We just don’t know what’s going to happen with all those other things that patients are potentially taking.

DR LOVE: Can you comment a little bit on some of the things you put on this slide? I thought it was pretty interesting.

MS GOODRICH: Okay. So adherence and monitoring. Assess and monitor adherence. So shared decision making, that’s a hot button here at ONS. If a patient is involved with the ultimate treatment decision, and you’re going to see here we really have a whole range of options for patients. Some of them are open ended. It’s daily or twice daily oral therapy. Others are finite. It’s a year of therapy with oral and IV. And so if the patient is involved with that decision making their more likely to be adherent and buy into that.

Health literacy. So in the old days, like Dr Love was saying, when we gave BR and FCR the patient was in our chair. We knew they were getting what they needed. They really need to understand that these drugs are important, and this is just as important as coming and getting — if they had had IV chemotherapy in the past, if they’re patients who’ve been around the block for a while, that it really is this is critical for them.

Open communication. So this is one of the great things about being a nurse practitioner is that we know who has transportation issues, who struggles financially, who doesn’t have a lot of social support. And really just making sure that patients know that you want them to do well, and if they’re honest about what their struggling with or what they’re worried about or problems that they’re having, we can solve them. We can get them hooked up with social work. We can get them transportation. We can help them.

And certainly there are a lot of financial toxicities with these drugs as well. There are lots of programs that we can access for these patients. So just knowing that we’re not going to be judgmental, we just need to know what’s going so that they can have the best outcomes possible.

And then I always ask people how many doses have you missed because then that’s an open door for not — did you miss any. How many did you miss? Because honestly who in this room has taken a full course of 10 days of twice daily antibiotics, right? I mean like so to think about being on this open-ended for years, they’re missing doses. So just having that open, accepting communication is really important.

DR LOVE: Yeah. When I saw that no judgment on your slide I was like that’s a great point. Camille, when you think about it you think about what Anthony just said. There are a lot of patients that are about to go on a 5 year or more ride, unless we change therapy, this is continuous therapy for life. What are some of the things you think about when you try to assess whether or not they’re taking their medication and how do you intervene?

MS BALLANCE: Well, I always ask them — we have a wonderful pharmacy that calls them, makes sure they get their medication, does additional education on top of what we do. But I always ask them are you getting your medication, are you getting it on time, is there a problem with it, to kind of start the conversation. Do you have a problem taking it? And most of the patients, like Amy was saying, if you’ve established a good rapport with them, which with CLL patients we see them for a long time.

So the nice — I would say the nice thing, there’s a little bit of luxury in the fact that we can start talking about treatment way before they need it, and I often do, right, if we see it coming, because a lot of times with CLL you see it coming. Like the white count’s going up. It’s not doubling, but it’s going up. They’re getting a little more anemic. You’re like okay, it’s coming so we can start talking about it and preparing them for it.

And then also sometimes our pharmacy will let us know if they haven’t picked up their meds, so that’s something. Then we can just have a conversation at the next office visit. But that doesn’t happen often, so…

DR LOVE: So Amy, you have a 66-year-old patient here. What happened? I guess it looks like the patient was diagnosed originally in 2010 but didn’t get treated until 2016.

MS GOODRICH: Yup.

DR LOVE: When did you first encounter the patient?

MS GOODRICH: So when did I first meet him? I met him in 2010, so this is where those long-term relationships with patients is very helpful. So he’s a good-risk CLL patient. We observed him for an extended period of time. He finally needs therapy. We only had ibrutinib in 2016, so we started him on ibrutinib. And he would come in and say he was tired. He was a little nauseated. He really downplayed the entire thing until he came in about — at 3 months, and I said how many doses have you missed, and he said the nausea’s really so bad that I’m skipping — I’m skipping a couple days a week because of the nausea. So this is where he was not — we had tried different antiemetics, but he really wasn’t being honest about how bad the nausea really was.

So we actually got our palliative care team involved, and we tried every antiemetic under the sun, and then finally we just dose reduced him, and his nausea significantly improved. He continues on ibrutinib to this day. He takes running promethazine, actually. That was the only thing that controlled him. We have talked to him multiple times about switching to acalabrutinib. He’s afraid to do it because he feels like this — ibrutinib is working. He’s got his nausea under control, so he has been on ibrutinib since 2016.

And so psychosocially the thing that made him stop taking it due to the nausea was that he wasn’t able to work, and then some of the antiemetics did work well but they made him sleepy during the day. He has a supportive wife, and at the time his daughter was a teenager. She’s not anymore. And then really this is where knowing him, and once I figured out he was really having significant nausea, then he opened up and again, we just dose reduced him and went on.

His fatigue did improve. His nausea’s well controlled. He’s satisfied with his side effect management. He’s very adherent. And like I said, he does not want to switch agents, and that really is okay. He’s tolerating it, and he’s responding.

DR LOVE: So Lowell, one of the themes that we’ve gotten into here, again it goes beyond any specific cancer, is dose reduction in oncology and the anxieties that patients have when we try to do dose reduction. Can you talk a little bit about how you reassure patients when you do that?

DR HART: Sure. I mean there’s so many agents that we use in many cancers that we find that everyone’s got their own dosage. I mean I tell everyone everyone’s body chemistry’s a little bit different. Just because it says this is where we’re supposed to start — in fact often, obviously, in the elderly patients that we see in Florida I won’t even start at the package label — package insert label with a lot of the drugs. The patients are going to be on these drugs for a long time.

So in the clinical trials, of course, you have to start full dose and move down, but outside of a clinical trial there’s no law that says you have to do things that way. So I think you have — there’s room for some judgment in these — in these patients. And generally speaking, I mean in CLL the proof is in the pudding, right? You can see how the patient looks, and you can see how their blood counts are. They’re not getting infections, they’re maintaining their weight, and they’re blood counts are stable, then whatever dose they’re on is an okay dose as far as I’m concerned.

DR LOVE: CLL is another really dramatic example of the potential value of participating in a clinical trial. You think about all the trials that these patients were on with BTK inhibitors that were not available clinically. And they experienced the benefit of the trials. We’re going to talk about some new agents that are not available right now that you can look at in a number of situations and say that would be the best therapy, but you can’t access it at this point. So really the value of being in clinical trials is number 1 in CLL.

Anthony, can you talk a little bit about how you approach a patient who’s about to start a BTK inhibitor? What are the — how do you explain to them how it works, what to expect, and what are some of the experiences you’ve had taking care of these patients?

DR MATO: Sure. So the BTK inhibitors are a unique class. I think we already talked about the kind of lymphocyte redistribution. It’s not — it was a major difference from what we had known from chemotherapy, where everything gets smaller and lower, hopefully. So when I talk to a patient about a BTK inhibitor we kind of talk about CLL in general, what’s driving the CLL, and touch on the different pathways inside the cell, the B-cell receptor pathway. I don’t think patients really want minutia, but just to understand that it’s a key pathway, that BTK is an important enzyme in that pathway. You block the signal, you allow cells to die, you allow cells to inappropriately migrate, which they go where they don’t want to go, and that’s certain — that leads to long-term disease control.

I think part of the explanation of the BTK inhibitors is the realization that it is a continuous — they are continuous therapies, and I think depending on where patients are getting their information, they have so much in their head about MRD, MRD, MRD, not something that these drugs achieve, and yet I can quote the best and longest-term data for them is a class outside of chemotherapy. And certainly no class has done better in terms of randomization against standard of care options as the BTK inhibitors have done.

There are now 2 on the market for CLL. There’s a third one that’s likely coming, zanubrutinib there in the noncovalents. It’s a crowded space, and it a world where we largely live in where particularly in the front-line setting we don’t really have comparative data. Fortunately in the relapsed/refractory setting we do, which has been really instructive to teach us about the adverse events associated with these drugs, which we already covered.

What else?

DR LOVE: Well, you had a couple of patients that you were referring to —

DR MATO: Oh, yeah.

DR LOVE: — so maybe we can talk a little bit about them. I don’t want to go through every single one of them. Maybe just the bottom line on some of these people.

DR MATO: Sure. So I included some patients that I thought were instructive from our practice. So this first one’s a 35-year-old with very poor-risk CLL, and poor risk defined by, again, the era of chemotherapy, who started ibrutinib in 2014 and remains on it today. This would never, ever have been achieved if I had given that patient FCR, for example, prior to the advent of ibrutinib. So it’s just instructive to the fact that this class of agents overcomes or at least partially overcomes the most poor-risk features associated with the disease.

DR LOVE: Before you go on, though, I mean it’s such a dramatic change, the difference between FCR and a BTK inhibitor. FCR is chemoimmunotherapy. I guess, Camille, have you given anybody FCR in the last few years?

MS BALLANCE: No, sir. I cannot say we have.

DR LOVE: But this was the standard therapy. Sir? Please. Anyhow, now I lost track of what I was saying. Anyhow — oh, FCR, brutal therapy. You talk about things, and if we’re talking about oncologists’ least favorite regimen, FCR is way up there. It gets replaced by an oral pill. It was amazing that this patient got to be treated with that.

What about some of these other people? And can you explain what mutated versus unmutated and kind of what it means? And also you used the term MRD. Can you explain that?

DR MATO: Sure. So mutated versus — well mutation and mutated are 2 different things. There’s lots of different mutations that — in the DNA that are associated with prognosis in CLL, but when we say you’re IGHV mutated versus unmutated the way I explain that to the patients is that the cells are a little bit more mature when they’re mutated versus unmutated. CLL is a mature B-cell cancer, but whether or not a cell has gone through the germinal center of a lymph node or not really helps to determine whether that B cell is very, very focused on a particular target or is still a little bit more generalized. That’s probably a way that I would explain it to patients.

Mutated patients traditionally did great with chemoimmunotherapy. Unmutated patients, so slightly less mature cell, didn’t do so well with chemoimmunotherapy. In the world of targeted therapies, particularly the BTK inhibitors, if you look at progression-free survival those curves are superimposable. So it’s another one where the risk factor is annihilated, is no longer a risk factor, with the newer therapies.

This patient that’s here, this 67-year-old receiving acalabrutinib who presented with palpitations and symptomatic hypertension, I just put that there as a reminder that while we talk a lot about ibrutinib and the adverse events, and the head-to-head data really does suggest that they’re lower with drugs like acala or zanu, those are still increased compared to the general population. And so if somebody’s on acala, and they call with a palpitation I take that every bit as seriously as I would somebody on ibrutinib, and the head-to-head data suggests it about 10% versus 16%. It’s not zero. So that’s why I included that patient there.

DR LOVE: So we’re going to move on now and talk about the other major modality that’s been introduced into CLL, and right now in general this is the other strategy that’s presented to patients who are requiring first-line therapy. And everything we hear, Lowell, I don’t know if you feel the same way, is basically in terms of efficacy, about the same. They haven’t been compared head-to-head but looks very effective but very different in that it’s short term.

DR HART: Yes.

DR LOVE: And very different in terms of the tolerability, a completely different story that we’re about to enter. Any thoughts though, Lowell, about the global view of short-term therapy versus continuous therapy? There’s been a lot made about the fact that BTK inhibitors are given for life, but hey, diabetic people — patients take things for life, hypertension, et cetera, and yet very strong feelings that a lot of patients and docs have. They kind of want to get treatment over.

Before we dive into the mechanisms, Lowell, any comment on what you see in terms of patient preference? I hear people say well older patients are maybe more accepting of BTK inhibitors and indefinite therapy. But what’s your clinical experience, Lowell?

DR HART: I think in general that’s true, Neil. I think and older patient who’s in their mid 70s, late 70s, when you’re talking about whatever drugs they’re on they’re on. They’re not going off any of their drugs until they’re too sick to take them, basically. So if you add on another drug and say, “This is your cancer drug.”

No obviously the issue can be these are expensive drugs now. We’re not talking about chlorambucil anymore. We’re talking about expensive drugs, and there can be copays and obviously all of these issues that come up with patients at the Medicare age and trying to find copay assistance for them and this and that and donut holes and all of that. So aside from those issues I think they’re very accepting of that. I think if you’re talking about a 50-year-old patient or some very young patients like you see there at Sloan Kettering, that’s a different story I think in a lot of them.

So in general I haven’t found a huge problem with the BTK inhibitors from people asking questions when am I going to get off. Now when they’re on it for a while, if they’re doing great, and they’re in what they think is remission, I’m not generally sending molecular profiling on those patients, then they do start asking well, the drug’s pretty expensive, when can I stop this drug. So that happens, not at the start, but a couple of years in. I don’t know what the other folks say, but that’s when I start to get those questions about when can I go off this drug, and I say not so much.

DR LOVE: Interesting. Amy, what’s your experience?

MS GOODRICH: So the same — the same issue, but what I actually find comforting, and this is a little twisted, when they stop for procedures they often have a bump in their white count and their lymphocyte count. And so that’s a real teaching moment to say hey, your disease is still there. This is just keeping it under the radar, and it’s keeping it stable. It’s not curing you. You are not in a deep remission, but you are in an adequate remission. So it is actually — that’s very tangible for patients when they stop, and they have a little bump in their lymphocyte count.

Venetoclax and Anti-CD20 Antibody Therapy

DR LOVE: So Anthony, I’m curious about your vision of how venetoclax actually works. It’s supposed to prevent cells — it’s an anti-BCL2 agent. I usually can’t figure out what these mechanisms of action graphics are. I picked this one because it has like smiley faces, but I still don’t think I understand it. Maybe you can — can you just conceptually explain in your own mind how these agents work and what you see in terms of clinical effect, how it compares to what you see with the BTK inhibitors.

DR MATO: Yeah. I was looking at that slide too thinking what was in Matt Davids’ head when he made that thing. Don’t tell him I said that.

DR LOVE: I like the tumor cells, the red tumor cell.

DR MATO: He was playing with every emoji on his phone probably when he made that.

So yeah. So CLL is like a cell that’s almost completely primed to die. Like the cell wants to die, and there are a few breaks that are put on that cell in order to keep it from dying. And essentially what venetoclax does is it just takes that break off and allows the natural apoptotic pathway within the cell to let the cell die.

These cells are really like poised to die. They’re mature B cells. They’ve done what they should have done, they shouldn’t be around, but the cells are smart, and they’re able to shut that mechanism or that key pathway off. So venetoclax undoes that break, and that’s the reason why if you take such a high, high does of it essentially you shut this pathway off — or turn it back on again probably is a better way to say it, and they all die simultaneously, which is why when we get into side effects we’ll talk about tumor lysis as a potential risk.

DR LOVE: And the one side effect, I mean when we first started to hear about it I’m like we never did this in oncology, is tumor lysis syndrome. So cells die so fast that you see toxicity issues. Can you talk a little bit about what tumor lysis syndrome — again, we’ve talked to your nephrologists about that, we’ve done programs with them, what tumor lysis syndrome is, Anthony, and how we prevent it?

DR MATO: I mean in one way it’s the — it’s ultimate success, right? It’s what we want, but it’s uncontrolled chaos. You kill cells, and all of the intracellular contents spill out into the blood stream, and they can cause the body to have a major issue. The 5 major — 4 or 5 major things that are seen in tumor lysis syndrome are hyperkalemia, so it could stop the heart; hyperphosphatemia, which can also cause arrhythmia and vascular issues and neurological issues; concomitant hypocalcemia which can cause cardiovascular and neurological issues; hyperuricemia, which can poison the kidney. And that combination of things can cause issues with the heart, the brain, and the kidneys, and all of those organs interact, so if you knock out one the other ones get affected too. So it’s a life-threatening issue that’s a result of being treated with a successful drug.

DR LOVE: Amy, can you talk a little bit about what you tell patients to expect in terms of receiving the therapy? It’s done differently in first and second line, but I think people are shifting more in general towards using an anti-CD20 agent, so obinutuzumab, which was done in the trial first, and then giving the venetoclax, and the idea is you kind of decrease the white count, decrease the nodes with the anti-CD20 so by the time the patient gets the venetoclax the tumor’s going to fall apart, there’s not as much to fall apart. But practically what do you tell patients, Amy, and kind of what do they go through as they kind of get into the groove so to speak?

MS GOODRICH: Right. So certainly they need to be aware of tumor lysis syndrome in terms of hydration, hydrating well at home. Everyone gets allopurinol, or just about everyone, unless they have a contraindication. And then there’s laboratory monitoring, at least for the first couple doses.

And so at the time you’re starting the venetoclax, whether you’re starting it first or you’re debulking with something else, there’s a great — in the package insert it’s really a little table of what’s their lymphocyte count, how big are their lymph nodes, you take into account their renal status, and you put them into low, medium, or high risk for tumor lysis syndrome. And it really spoon feeds you through how often are you checking labs, how much should they be hydrating, what are you doing preventatively for tumor lysis syndrome.

But those high-risk patients get admitted for their at least 20 and 50 mg ramp up. Most patients today, again, as Dr Love said, when we lead in with obinutuzumab they get debulked. So even those high-risk patients typically by the time they’re ready to start their venetoclax we can manage them as outpatients, they shift down on that severity or their risk — that risk table that’s in the package insert.

Patients really need to understand that they’re going to be coming. They’re going to spend a long day with you because they get labs pre, they take the dose, and then they get labs 6 to 8 hours later, and then they come back for a 24-hour. So it is lots of trips initially, for the first 5 weeks, but then after that it tapers off. And the real silver lining here is that in general this drug is quite well tolerated. There’s not a lot of nausea. There’s not a lot of diarrhea. Like there’s not bleeding. There’s some cytopenias. But really once you get through that labor-intensive and time-intensive beginning it really is a very well-tolerated drug.

DR LOVE: Before I call on Lowell I’m trying to remember if this was a dream, or it actually happened. The whole last 2 years to me, I’m not sure what really happened, but I’m trying to remember did you have a patient that you tried to get on venetoclax who was like in a nursing home, and you had — Amy?

MS GOODRICH: Oh, yes. Oh my gosh. When COVID happened I had a lady who was in her ramp up when COVID happened, and I didn’t know she lived in — I knew she lived in an apartment, but it was a senior facility, and they locked down, and she could not get out. And I worked with her. They had a health suite, and there was a nurse practitioner in that health suite, and she saved me, and we were able to monitor her labs, and she ordered them stat, and they went to the local hospital.

And we were really able to get this lady — because she was on like 20 mg when — it was nothing. If she had been on 100 or 200 we may have just left her there. But when we had started — we started the drug, and if she was going to benefit from it we needed to keep going.

So that’s where Camille talked about you’ve got to pick up the phone. If you’re coordinating this care you’ve got to pick up the phone, talk to the PCP, talk to the cardiologist, talk to the NP at the facility. And people are more than happy to help. They’re more than happy to switch up drugs if we need them to. I have collaborated more since we have all these oral drugs than — I’ve been in oncology since 19 — I’m going to date myself — 89, and I have collaborated more about concomitant medications and patient care in the last — since 2014 than I ever did before.

DR LOVE: Yeah. When we started yesterday morning with prostate cancer we heard a case about a patient who was a forest ranger in the depths of California, and the nurse practitioner got therapy started with a local doc because the forest ranger didn’t want to come out of there. Metastatic disease, now in complete remission. He’s never met the patient. He completely dealt with the patient on telemedicine and through the primary care doc. Lowell?

DR HART: Well one of the questions I just want to ask the others in the group, this comes up in our practice setting, is getting lab results for these patients in real time. Now it’s easy to do in an academic or major center, but the majority of the people here are going to be giving this drug to people in a community setting, where you don’t always get real-time chemistry results back on a patient. It may take a while to get it back. So what would be the advice about doing these patients — when you say the medium-risk patients as an outpatient, if you expect to have a difficult time getting laboratories back?

MS GOODRICH: So I actually — I have patients get their pre-labs the day before.

DR HART: Right.

MS GOODRICH: And most patients have a local hospital that they can go to, and their labs turn around just as fast as ours do. Most patients really have access to that. You just have to be — I think you have to be creative.

DR HART: Right.

MS GOODRICH: But it is a problem to get labs back in a timely fashion.

DR HART: And something you have to plan out ahead of time before the patient comes in. You don’t want to get caught by surprise and not have any lab results.

MS BALLANCE: We’ve actually ramped patients up before and then sent them back to their primary because of the stat lab issue. I think we’re doing less of that now, but particularly when we first started giving it a lot that that was — we were — yeah. We were seeing them for about 6 weeks and then sending them back.

DR LOVE: Before we ask Camille to go through some of the things she thinks about when she starts a patient on this type of regimen I’m just kind of curious in terms of we were talking about trying to get these people through the therapy, but also the issue of the fact that it’s going to be hopefully over in a year. But the other issue that’s a big, controversial issue, Anthony, is do you really stop at a year, which is what was done in the trial. And one of the issues that’s been discussed a lot is so-called MRD (minimal residual disease) measurements. They’ve been used a lot in these venetoclax trials.

And there are patients at the end of a year who have disease that you can detect, you can’t see it otherwise, but you can detect it in these MRD assays. And a lot of controversy, in the trial itself they stopped the therapy even if they were MRD — they didn’t look at MRD. Now people in the community are getting these assays, and they see the disease is still there. There are some people who want to continue therapy. Can you talk a little bit, Anthony? The whole object is to get off the therapy. Are there situations where you would continue it?

DR MATO: Yes. So MRD is minimal residual disease, and all it is is really a general term for depth of remission. There’s not one absolute definition, and across the studies you’ll see they define it differently, 1 in 10,000, 1 in 100,000, 1 in 1,000,000, depending on what assay you can use.

While I’m a huge proponent of venetoclax, I use it all the time, I’m not so much a fan of the one size fits all cookbook, everybody gets a year and then you stop. And I’ve always been a subscriber to the idea that we probably should be giving it based on depth of remission. If you can get to 10^-6 at 6 months maybe you don’t need to have a year’s worth of therapy. Of course whatever I’m saying is not standard of care. Of if you’re at a year, like you said, and you’re positive, maybe those are the patients who would have a slower rate of progression if they just stay on drug.

All of our studies at MSK have an MRD component in terms of decision making. We have 1 called Veneto-STOP, which you can imagine like the makers of venetoclax didn’t like the name of that study. They didn’t fund it. I have a little stop sign next to the — but that trial let’s us stop based on depth of remission, 6 months minimum, but you could also stay on it longer if you’re not MRD negative or undetectable.

So it’s an emerging topic, and I do think ultimately we will be making decisions based on that.

DR LOVE: So Camille, you put together some thoughts about starting people on these types of regimens, and you cited a case here of a 71-year-old woman with SLL, which we haven’t talked about that term. But CLL involves both the nodes, you can have lymphadenopathy, as well as the white count. And in patients who have more predominant nodes and not that much — they’re called SLL. What about this patient? How did she present?

MS BALLANCE: So this was a woman who had been on watch and wait for approximately 3 to 4 years. Again, she has SLL, like Neil was saying, so she had really bulky cervical adenopathy. You could see it across the room, okay? But her counts were fine. CBC was normal.

And she had had some bulky adenopathy, but it was getting worse, she was getting more fatigued, so we knew that it was time for treatment. And she did not have 17p, so —

DR LOVE: Before you go on, I meant to bring that up. What would it have meant if she did have “17p”?

MS BALLANCE: Then we probably would have put her on a BTK inhibitor to start with as opposed to talking about do you want to do a BTK inhibitor or do you want to do venetoclax and obinutuzumab. So I talked about both with the patient. She decided she wanted to try the time-limited therapy, and so off we went.

So we started her on therapy, and — so she — anybody that hasn’t given obinutuzumab, you give — it’s 1000 mg flat dose. You give a test dose on day 1, and that’s because there’s a lot more infusion reactions with obinutuzumab than there is with rituximab. There just is. And so — and also you have to — even though we’re debulking them on the front end, to prevent tumor lysis if a patient has really bulky disease you still have to assess for — or you still should be assessing for tumor lysis the next day because they can still lys with monoclonal antibodies. Not as often as with venetoclax, but they do.

So anyway, she came in, had a reaction, but managed to get her whole first test dose. She got through it. This is an active 71-year-old woman, good family support, good husband, otherwise healthy, walked into the clinic. So she gets through it.

The next day her husband her husband wheels her in in a wheelchair, okay? And her blood pressure was 79/47, her heart rate was 130, and she wasn’t feeling so hot, right? So we had already — I had already had lysis labs ordered. We had sent them stat. Her uric acid was 14. Her LDH was 2,000. Her creatinine had gone — her baseline creatinine was about 1.2. It had bumped to 1.7. I was honestly surprised it wasn’t higher with the way that she looked. And her electrolytes were stable, surprisingly. But those 3, I’m like well, we are lysing. We are there.

So she — we started fluids. Now this was in February. We were having a huge COVID spike in February. I was really trying not to send this woman with CLL to the ER that was packed with COVID patients at the time, right? So we gave her a liter of fluid. Her blood pressure — and we were able to also get rasburicase, which was great, the fact that we were able to get it for the clinic. We gave her rasburicase, we ended up giving her 2 liters of fluid, and she turned around. I mean her blood pressure stabilized. Her heart rate came down. She was feeling better. She had really good — she had really good social support so we were able to send her home, although I had already — I thought for sure we were going to have to admit her to the hospital. I’d called one of the attendings and was like “so this is what I’ve got going on here.”

DR LOVE: And this is all from the obinutuzumab?

MS BALLANCE: This is all from the obinutuzumab.

DR LOVE: Not venetoclax.

MS BALLANCE: We didn’t even get to the venetoclax, right? So she came back in the next morning.

We discharged her with her husband like if you feel bad at all you need to go to the hospital. You need to call, hydrate overnight. She came back in the next day, and her — she was doing much better. Her uric acid was less than 1, so the rasburicase worked very well. Her creatinine had gone back down to baseline. She was feeling a lot better. We gave her extra fluids because her LDH was still up. It was better, but I think it was still like 1,700.

So we gave her extra fluids. She did — she did really well, and then brought her back on Monday to see Dr Flinn, and we started her on a BTK inhibitor. We’re like that is a wrap. And even if we had tried to rechallenge her not only would our nurse — the nursing staff would have killed us, but she wouldn’t have done it anyway. She was so anxious over that, and that was a very — let me just preface this by saying this is a very extreme example. Most patients, even if they react, they do very well, we get them through, and like Amy was saying, it’s very well tolerated. But this woman clearly has stood out in my memory because it was interesting.

DR LOVE: Anthony, any response to this case? Anything that could have been done differently? Have you seen, Anthony, this kind of TLS just from obinutuzumab?

DR MATO: Well, I think it’s not that well known, but if you look at the original ven study front line, obin/ven, the CLL14, there was a small percentage of TLS that was reported on that study. All of the cases were from the obin not the venetoclax. And so TLS is not a new concept to venetoclax. Any drug that’s effective can cause it. So when we give obin we check labs afterwards, 8 hours usually, on the first day with that 100 mg dose because we do sometimes see some electrolyte abnormalities. And so it’s just a really effective antibody. It can happen.

I might have considered rechallenging the patient at some point, but I probably would have done it in the inpatient setting because this was — this was very dangerous, what happened.

DR LOVE: Well maybe in the future.

Future Strategies

DR LOVE: And speaking of the future, one of the things that’s an obvious question is well what about putting them together, BTK and venetoclax, and there are tons of trials looking at that. This is an example. Anthony, can you kind of just provide an overview of this whole concept of fixed-duration therapy but now including a BTK inhibitor combination?

DR MATO: This is — this is a window into the future. Originally that concept came from MD Anderson with ibrutinib and venetoclax. But this CAPTIVATE trial is 1 of 2 trials that are kind of the most well developed ibrutinib/venetoclax combinations. CAPTIVATE was 2 trials. One was a fixed-duration arm, the bottom box there, where everybody got 3 months of ibrutinib and 12 months of combo. And then the top one was the MRD-driven approach, where you got the same 15 months of therapy, and then based on MRD there were decisions made about continuing on ibrutinib or being randomized to ibrutinib and I & V.

What’s nice about the combination is that it is pretty active. You can see there the high rates of undetectable disease. The CAPTIVATE study was a younger population. The randomized trial called GLOW, I don’t know if it’s part of our deck or not, was a randomization versus chlorambucil and obinutuzumab, and that trial was an older patient population. And comparing and contrasting you see different rates of MRD/undetectable disease, and different side effect profile. The older you get the harder it is to put multiple doublets and triplets together and tolerate them very well.

So I suspect this will play a role in CLL. It will not revolutionize the field like the introduction of ibrutinib did in 2014.

DR LOVE: Lowell, any thoughts about the idea of combining the 2? In a way this is something that happens a lot in oncology. Metastatic breast cancer you combine agents, and in a lot of instances they use only single agents because the idea is maybe patients would do better if you do single agents sequentially. Maybe in the long run patients would do better getting a BTK inhibitor followed by venetoclax or vice versa compared to combined. How do you, being in practice, think about how — maybe this is going to get approved, the GLOW study, it’s in your slide deck, maybe is going to get approved. How would you decide whether to do it or not, Lowell?

DR HART: It’s hard to — hard to beat a 98% response rate, and it’s an all-oral regimen, which is nice. It’s a fixed duration regimen, right? So I think it’s going — I mean on the other hand there’s going to be some financial toxicity from using these drugs together. You have to have pretty good oral drug coverage. But I think it’s — I think, like I said, it’s not going to revolutionize the field, but it’s going to be an option out there for somebody who wants 2 very potent drugs at a fixed duration of time. I think it’s going to be quite attractive. I think it’ll get used.

DR LOVE: So right now really the only time you’re seeing this is in clinical trials. Amy, have you had patients get both BTK and venetoclax at the same time in a trial?

MS GOODRICH: Yeah. Not on trial, but in reality.

DR LOVE: In reality, wow.

MS GOODRICH: In reality, yes. I’ve got a few patients who are quite elderly. They will not ever be eligible for clinical trials. They will not be CAR T or any novel — other novel therapy candidates who had been on a BTK and progressed and then were responding to venetoclax. And some of them were before we added the anti-CD20. So if patients like that, who we really don’t have another thing to give them that’s going to be effective and safe, we will add a CD20 to try to get more bang for our buck out of the venetoclax, so layer these things together. But then if they continue to progress we’ll add a BTK back, and you can really milk some more time out of it that way. It’s unconventional, but when you have these older folks where you don’t have other options you get creative.

DR LOVE: So we’re going to talk more about CAR T in our lymphoma webinar that we do after the meeting, and of course that’s really revolutionized particularly the therapy of diffuse large B-cell lymphoma and mantle cell lymphoma. Actually, CAR T is very effective in CLL, it’s just that BTK and venetoclax came along, there are not that many people who kind of get out there that need it, although it is available.

But we do see patients, Anthony, who end up being resistant both to venetoclax and BTK, double progressors so to speak. Really — approved options in that situation relatively limited, but some really exciting opportunities.

Can you talk a little bit about the new BTK inhibitors that are coming along? The one I guess we’ve seen the most experience is down there in the lower right, pirtobrutinib. You’ve done a lot of research on that. Super exciting. Maybe you can talk a little bit about what it is and where you see it heading.

DR MATO: Sure, yeah. It’s probably the most exciting drug I’ve worked with from the beginning. We treated the first couple patients with pirtobrutinib right before COVID started. It’s called a noncovalent or reversible BTK inhibitor. Drugs like ibrutinib or acala, once they bind to BTK they never come off. It’s an irreversible bond. But this drug comes on and off, and it binds in a different location so that it was designed to be very specific for BTK, but it doesn’t have the same mechanism of binding, and so it can overcome the known resistance mechanisms to the irreversible or covalent BTK inhibitors.

So it has that really — it had that really great potential before it was tried in patients to have very few side effects and to address an unmet need, the patient population that you’re mentioning, the double-exposed patient population.

I can speak to its clinical activity. There have been about 252 patients treated with this drug with CLL, and the response rate is 68%. And the further you follow these patients — that’s like all patients, and all of them had seen a prior covalent BTK inhibitor, the further you follow them out the deeper the responses tend to get. You can see that waterfall, like each of those are individual patients. There’s a really significant reduction in the lymphadenopathy.

And 41% of patients on this trial not only had a BTK inhibitor, they also had venetoclax, and yet we see the median progression-free survival isn’t reached. Even in patients who failed 5 prior therapies, I never thought I would say this, somebody who had a CD20, chemo, a BTK inhibitor, PI3K inhibitor, and venetoclax, they’re still getting that same benefit from the drug. So I do think that this class, or this agent maybe in particular has the chance to be another paradigm shift, and patients who might have had a survival of 6 months in my practice are now like on cycle 40 of LOXO-305, and it’s really incredible to see that.

DR LOVE: And we’ve talked about the fact that this graph is a so-called waterfall plot. So each of these sticks is a patient. And this is measuring response or not. So it if goes up it’s getting worse, it’s getting bigger, the white count’s going up. If it goes down it’s good. And you can see you don’t see waterfall plots like this all the time, almost everything going down.

Lowell, I can remember, it wasn’t that long ago that there wasn’t BTK or venetoclax, it was only like 6 or 7 years ago, and yet we were seeing these trials, and everybody’s like I want to use that drug, and it wasn’t approved. I kind of am starting to feel the same way about this drug, like you see a patient who’s — you see this, you want to give it to them, yet the only way you can do it is on a trial.

DR HART: Absolutely.

DR LOVE: And of course you’ve really set up the trial system in the Florida Cancer Specialists.

DR HART: Sure.

DR LOVE: Any comment about how — this issue of what do you do when you see an agent but it’s not approved?

DR HART: Well, as you said, we work closely with the Sarah Cannon group in Florida, and on my academic side I don’t see blood diseases there, but a very active program of research in leukemias/lymphomas also. So I think that’s very key. I mean this is obviously an outstanding drug for a tough to treat population. So I think we all have to be aware of that.

Now obviously not every patient is going to be a candidate for clinical trials, unfortunately. Now sometimes you can, if you make enough effort, you can get these drugs on a compassionate basis. Now I can tell you from experience that’s not easy or fun to do, and I try to avoid it whenever possible because of the paperwork which tends to stack up. But occasionally, and if I could make a plea to the powers that be, we should make that somewhat easier for patients to obtain these drugs compassionately without excess paperwork.

DR LOVE: And I should mention that Camille is with the Sarah Cannon Research Center, and the Florida Cancer Specialists is one of the groups that works with them. Camille, have you used pirtobrutinib?

MS BALLANCE: Yes, I have. We’ve used it in a couple of elderly patients that have done really well with it. No just elderly, but there’s one in particular, she’s 86 —

DR LOVE: That’s not elderly.

MS BALLANCE: — other comorbidities and did really well with it. She was on it for about 2 years, and now she’s on another trial, actually — or a year and a half.

DR LOVE: Do you see the arthralgias and other quality-of-life issues?

MS BALLANCE: No. No. She tolerated it really. And even the other patients that we’ve had on it tolerated it remarkably well.

DR LOVE: So Anthony, the other modality we talked about, again, so much excitement in oncology, but we’re doing so well with CLL I’m not sure it’s ever going to really come here. I think one of the first patients that got CAR T had CLL and had a great response up there at Penn. But can you talk a little bit about what CAR T therapy is and what we know about it in CLL?

DR MATO: Sure. CAR T — well CAR stands for chimeric antigen receptor T cell, and this is another thing that would have been science fiction a decade ago, where we’re able to take a patient’s T cells that are collected autologously, transfect them with a virus, and have that virus express a whole new gene that didn’t exist before to train the cells to kill a specific cancer. In the case of CLL and lymphomas — well, in lymphomas, the approved products are against CD19, which is commonly expressed on B cells.

So essentially you’re training the patient’s immune system to kill the cancer that’s the problem. CLL is a situation where I think finally we’re at the time where CARs will be relevant. CARs had bad timing. They came — they hit the news right before ibrutinib was approved, and so this paradigm shift happened without them because it’s so much easier to prescribe a pill.

But now we’re in a situation where we have a lot of young patients, they’re cycling through multiple targeted therapies. Even pirtobrutinib, as great as it is, patients will ultimately progress beyond that when they’re in the relapsed/refractory setting. So there can be long-term disease-free remissions, even maybe cures with this.

And my personal interest in CAR T at the moment, working on developing cells to bring these — studies to bring these to even earlier lines of therapy for patients. Because the other problem in CLL, if you want to describe it as a problem, is that the therapies and their immune systems aren’t so great, so their T cells don’t function so well, so the longer you wait you’re probably getting a damaged product back into the patients. And so it’s kind of a crux. You have to find the optimal time to give it, but at the same time you may not want to give it too early.

DR LOVE: Interesting. So Amy, I want to conclude with some thoughts you put together about patients who’ve exhausted approved treatment options and the role of clinical trials.

MS GOODRICH: Right. So what I tell patients, what I talk to patients about, is that all of these new classes and these new agents have completely changed the survival and the outlook for patients with CLL, particularly the ones with those poor-risk factors that were more, like Anthony said, more applicable in the days of chemoimmunotherapy.

And so these new generations have been successful. Many patients, and certainly like the gentleman that I — who was diagnosed in 2010. So we were talking to him about chemoimmunotherapy when he was initially diagnosed as what we would do. And so he was able to benefit from these new drugs. And many patients when they were diagnosed, these drugs didn’t exist, so they have seen — and they’re on all these LISTSERVs and all these sites, and they are really very aware that things are changing rapidly, and it’s been done through clinical research. And it’s voluntary. I always say that. It’s voluntary. You can go off at any time, but this gives you an opportunity to get the latest greatest drug.

And so this — go ahead.

DR LOVE: No. Go ahead.

MS GOODRICH: And so this patient, he is an extreme example. He was a young guy who was diagnosed in 1997, 17p deletion. He literally got every therapy under the sun. He was on a lenalidomide trial. He got CAR T.

DR LOVE: He got FCR too.

MS GOODRICH: He started out with FCR because that’s all we had. He got an allotransplant, donor lymphocyte infusions, lenalidomide on a trial, bendamustine/ofatumumab, more DLI, he got CAR T on a trial, more bendamustine. He got ibrutinib in 2013, so he got that on a trial. He started venetoclax, that was also on a trial, in 2018 because that’s how we met him. He would go — he started out at the National Cancer Institute. He got his first CAR T I think at Baylor. He would go to University of California San Diego to see Tom Kipps. He would go to Ohio State and go on trials there.

We met him when venetoclax, the trial he was on, went on label, and he had to get it as standard of care. He was a really tough patient. He ended up dying of infection. He had fungal pneumonia. He had — he was tough because he had these providers all across the country. He was in constant contact with them. He was an extreme case for sure. He knew every trial that was going on, what was coming, when it was going to be open, where. He was really like a walking encyclopedia of the landscape of CLL. I don’t think he ever came to see you.

DR MATO: I don’t think so.

MS GOODRICH: Anyway. He was tough because he was just — he was on a mission to live, and he never thought that he was going to die. He never thought he would run out of treatment options. And it was kind of sad because he was single. He was out of contact with his siblings. He had no children. He was man alone just on this mission to get on every trial humanly possible. He ended up dying of an infection.

DR LOVE: What was it like taking care of him?

MS GOODRICH: It was really tough because he — it was very hard because he was very aloof. We were just plugging a hole for him. And he would — Anthony said this, Dr Mato said this, and so and so said this, and I called them last week, and it was just chaos. This guy was just chaos trying to figure out who he had been in touch with.

And he was really trying to get on a CAR T trial again at Baylor, and we were giving him alemtuzumab, for those of you who have not been around the block, probably the nastiest monoclonal antibody that we have ever had. It’s the only thing he had not gotten. And he ended up dying of infection.

DR LOVE: So I want to thank the faculty. Thank you for attending. Come on back tonight at 6. We’re going to talk about breast cancer and then AML.